Keywords

Mouse monoclonal antibody · Chimeric antibody · Humanized antibody · Human

antibody · Therapeutic applications of monoclonal antibody

22.1

Introduction

Production of monoclonal antibodies (MAbs) has evolved since the first demonstra-

tion by Köhler and Milstein at Medical Research Council (MRC), Cambridge, UK,

about the feasibility to obtain hybrid cell clones capable of growing in culture and

secreting antibodies of predefined specificity by somatic cell hybridization (Köhler

and Milstein 1975). For this discovery, Cesar Milstein and George J. F. Köhler won

the Noble Prize in Physiology or Medicine in 1984 along with Niels K. Jerne. The

MRC, UK, awarded its first Millennium Medal to Cesar Milstein in 2000 in

recognition of his groundbreaking work, and its Chief Executive Professor Sir

George

Radda

commented

that

“the

discovery

of

monoclonal

antibodies

revolutionized biomedical research and sparked an international billion-pound bio-

technology industry. No other MRC scientist has made such an outstanding contri-

bution to Britain’s science, health and wealth creation” (The Times, London,

26 March 2002, Obituaries-Cesar Milstein). MAbs are homogeneous in nature and

can be produced in large amounts. Due to the high specificity of MAbs, these are

useful in targeting tumor cells and microbial pathogens. These can be used as either

stand-alone or adjunct therapy in conjunction with the conventional therapy. In

cancer patients as compared to radiation and chemotherapy, immunotherapy by

MAbs may have less side effects. Furthermore, therapeutic MAbs are also useful

for immunocompromised hosts, elderly persons, and pregnant women. The first

murine MAb OKT3™that recognizes a nonpolymorphic subunit of human T cell

receptor, CD3, was approved by the US Food and Drug Administration (FDA) for

use in human subjects to prevent rejection of renal allografts (Chatenoud 2003). In

addition, mouse MAb generated against CD20 on B cell was also used in patients

suffering from non-Hodgkin’s lymphoma. Though murine antibodies have exquisite

specificity for therapeutic targets, they do not always trigger appropriate human

effector functions of complement and Fc receptor. Further, murine antibodies are

recognized as foreign by the human immune system evoking human anti-murine

antibody immune response, thus cutting short their therapeutic window (Shawler

et al. 1985). However, limitations in the use of murine MAbs for therapeutic

applications can be overcome by using newer protein engineering and molecular

biology tools and advances in cell biology to develop more human-like MAbs with

lesser immunogenicity. Evolution of the therapeutic MAbs is schematically shown

in Fig. 22.1. In this chapter, we will briefly describe the strategies to produce

chimeric, humanized, and human MAbs and their therapeutic applications. In

addition, novel MAb variants and their potential application will also be discussed.

The current and forecasted market of therapeutic MAbs will also be presented.

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S. K. Gupta and P. Chaudhary